The previous cycle of this program project examined effects of NGF gene transfer on neuronal degeneration in primate models of aging and cholinergic degeneration, leading to two human clinical trials of NGF gene transfer in Alzheimer's disease (AD) and anatomical confirmation of the hypothesis that degenerating neurons in AD exhibit trophic responses to neurotrophic factors. Thus, this program project has led to translation of novel, potential therapies for AD. This renewal will evolve its focus to two new efforts that both retain a focus on gene delivery in primates, and expand the focus to determine whether emerging and intriguing data from rodents in other aspects of this program are relevant to the primate brain. First, we will determine whether the neurotrophic factor brain-derived neurotrophic factor (BDNF) enhances neuronal function and prevents neuronal loss in the primate entorhinal cortex and hippocampus. Second, striking findings from rodent studies in this program project suggest that physical activity influences neuronal structure, neurogenesis and cognition. To determine the relevance of these findings to complex primate systems, we will determine whether physical exercise enhances hippocampal neuronal structure, synaptic markers, neurogenesis and cognition in aged monkeys. These findings could be important in modifying populational risk factors for dementia, and could establish a rationale for activity enhancement in AD. Aim 1: Determine whether BDNF gene delivery prevents neuronal degeneration, enhances hippocampal neurogenesis and improves learning and memory in aged primates. Aim 2: Determine whether AAV-2 mediated gene delivery is a safe and effective means for long-term BDNF delivery to the entorhinal cortex for future clinical implementation Aim 3: Determine whether physical activity in aged primates enhances cognition, neuronal structure and neurogenesis.